Abstract
The human immune system presents remarkable inter-individual variability in response to pathogens or perturbations. Recent high-throughput technologies have enabled the identification of both heritable and non-heritable determinants of immune response variation between individuals. In this review, we summarize the advances made through the Human Functional Genomics Projects (HFGPs), challenges and the need for more refined strategies. Inter-individual variability in stimulation-induced cytokine responses is influenced in part by age, gender, seasonality, and gut microbiome. Host genetic regulators especially single nucleotide polymorphisms in multiple immune gene loci, particularly the TLR1-TLR6-TLR10 locus, have been identified using individuals of predominantly European descent. However, transferability of such findings to other populations is challenging. We are beginning to incorporate diverse population cohorts and leverage multi-omics approaches at single cell level to bridge the current knowledge gap. We believe that such an approach presents the opportunities to comprehensively assess both genetic and environmental factors driving variation seen in immune response phenotype and a better understanding of the molecular and biological mechanisms involved.
Highlights
The last decade has witnessed a series of cohort-based studies that emphasized the role of both host and environmental factors such as diet and lifestyle in determining human phenotypes in health and disease conditions
Aguirre-Gamboa et al (2016) by investigating environmental and genetic factors on immune cell populations in peripheral blood and immunoglobulin levels, identified eight independent genomic loci associated with cell count variation and these QTLs overlapped with GWAS single nucleotide polymorphisms (SNPs) already known to increase susceptibility to immune-mediated diseases [16]
Even though the advent of the human functional genomic projects (HFGPs) had an unprecedented impact on our knowledge, bringing into light the genetics and non-genetic host factors contributing to inter-individual heterogeneity in immune responses, the expansion of such studies to incorporate diverse populations is needed to realize the personalized medicine in every population
Summary
The last decade has witnessed a series of cohort-based studies that emphasized the role of both host and environmental factors such as diet and lifestyle in determining human phenotypes in health and disease conditions. A cQTL (rs11141235) of Candida-induced IL-6 at the NAA35-GOLM1 locus was associated with susceptibility to candidemia These studies strongly suggested the causal role of genetic variants in infectious diseases that affect gene expression and cytokine responses in a context-specific manner. Until the inception of the HFGPs, there have been no comprehensive studies in humans to investigate the basis for inter-individual variability in cytokine responses after stimulation with pathogens Results from this pilot study of 200 Functional Genomics (200FG) cohort from our group [12] indicated the feasibility of identifying disease relevant SNPs and genes using this approach, the study itself had several limitations. To tackle some of these challenges the 500 Functional Genomics (500FG) study was initiated
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